The present invention relates to an aqueous preparation containing vitamin A or its derivative which may be used for the treatment of dry eye syndrome represented by lacrimal hyposecretion, squamous metaplasia and the like. More specifically the present invention relates to an aqueous preparation containing vitamin A or its derivative and having a stability which allows the use of the preparation as an ophthalmic pharmaceutical preparation.
The cornea is an avascular tissue forming the front surface of the eyeball, and it has transparency and a constant curvature which are necessary to correctly introduce light from the environment into the eyeball. To maintain transparency of the cornea, it is the fundamental requirement that each of the 5 layers constituting the cornea, i.e. the corneal epithelium, the Bowman's membrane, the corneal stroma, the Descemet's membrane and the corneal endothelium, is regularly arranged and performs its normal physiological functions. Since the cornea is an avascular tissue, its supplies of nutrients required for the maintenance of its functions are dependent on the perilimbal capillary loops, the aqueous humor and the tear fluid, and the corneal epithelium, in particular, is exclusively dependent on the tear fluid for the nutrient supplies. In addition, the corneal epithelium is protected by the tear film from the air and the mechanical stimulation which may be caused by friction with the palpebral conjunctiva.
Since the corneal epithelium is constantly exposed to the air, except when the eyelids are closed, the water in the tear fluid which covers the cornea is constantly lost by evaporation, and the loss is supplemented by a continuous production of the tear fluid. The production of the tear fluid is made cooperatedly by the lacrimal gland, the goblet cells and the meibomian glands. Their functions may be lowered by a variety of extraocular disorders and systemic disorders such as autoimmune diseases as well as aging. When the function to produce the tear fluid is lowered, the corneal epithelium tends to become dried, the physiological state of the corneal epithelium is thus disturbed, and the occurrence of inflammation is promoted, which may lead to corneal injury, corneal opacification or vascular infiltration into the cornea. Moreover, it is known that since the cornea is an extremely sensitive site, only a very slight tendency to dryness may cause an uncomfortable sensation such as photophobia, pain, a feeling of the presence of a foreign body and the like, thus hindering daily life, and may cause severe symptoms in some cases.
Vitamin A and its derivatives are known to be effective on such pathological states [e.g. J. L. Ubels et al., Current Eye Research, 10 (4), 1049 (1985)], and based on these reports, topical preparations which contain an effective amount of vitamin A or a derivative thereof having vitamin A activities (in the description hereinafter, the simple wording "vitamin A" refers to "vitamin A and its derivatives having vitamin A activities ", unless derivatives of vitamin A are clearly excluded according to the context) have come to be applied. Among, others, preparations in the form of aqueous eye drops have been needed so as to allow appropriate administration by patients themselves, since it is necessary to repeatedly administer vitamin A over a period of time in order to treat patients with a variety of uncomfortable symptoms and severe damages caused by the tendency to dryness of the cornea and conjunctiva.
However, vitamin A and its derivatives are extremely unstable compounds. It is known that, inter alia, in aqueous preparations, their loss is likely to be elevated to an extreme degree due to the adsorption to the container as well as decomposition, thus resulting in a rapid degrading of product quality during storage. Consequently, it is extremely difficult to produce an aqueous preparation stably containing an effective amount of vitamin A. Thus, a vitamin A aqueous preparation which is satisfactory has not been put into practical use.
The inventors made an extensive study to solve the problem. Finally, the inventors have succeeded in solving the thus-far insurmountable problem and produced a stable aqueous preparation which can be used as an eye drop by incorporating, during production of a vitamin A preparation, a buffering component selected from the group consisting of phosphoric acid, boric acid, citric acid, glutamic acid, .epsilon.-aminocaproic acid and the alkali metal salts thereof, a non-ionic surfactant and a chelating agent, and adjusting the acidity in the range of pH 5 to pH 8, and filling into an air-tight container made of polypropylene or polyethylene terephthalate.